This invention relates to new and useful optically-active hydantoin derivatives in the field of medicinal chemistry. More particularly, it is concerned with certain novel 8-substituted derivatives of D-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, which are of especial value in view of their therapeutic and physical-chemical properties.
In the past, various attempts have been made by numerous investigators in the field of organic medicinal chemistry to obtain new and better oral antidiabetic agents. For the most part, these efforts have involved the synthesis and testing of various heretofore new and unavailable organic compounds, particularly in the area of the sulfonylureas, in an endeavor to determine their ability to lower blood sugar (i.e., glucose) levels to a substantially high degree when given by the oral route of administration. However, in the search for newer and still more effective antidiabetic agents, little is known about the effect of other organic compounds in preventing or arresting certain chronic complications of diabetes, such as diabetic cataracts, neuropathy and retinopathy, etc. Nevertheless, K. Sestanj et al. in U.S. Pat. No. 3,821,383 do disclose that certain aldose reductase inhibitors like 1,3-dioxo-1H-benz[d,e]-isoquinoline-2(3)-acetic acid and some closely-related derivatives thereof are useful for these purposes even though these particular compounds are not known to be hypoglycemic. These particular aldose reductase inhibitors function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses (like glucose and galactose) to the corresponding polyols (such as sorbitol and galactitol) in the human body. In this way, unwanted accumulations of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, peripheral nervous cord and kidney of various diabetic subjects are prevented or reduced. As a result, these compounds are of value as aldose reductase inhibitors for controlling certain chronic diabetic complications, including those of an ocular nature, since it is already known in the art that the presence of polyols in the lens of the eye leads to cataract formation together with a concomitant loss of lens clarity.
More recently, there is disclosed by R. Sarges in U.S. Pat. Nos. 4,117,230 and 4,130,714 a series of spiro-hydantoin compounds which are useful as aldose reductase inhibitors for controlling certain chronic diabetic complications. The key compound disclosed in U.S. Pat. No. 4,117,230 is dl-6-fluoro-[chroman-4,4'-imidazolidine]-2',5'-dione, while the key compound disclosed in U.S. Pat. No. 4,130,714 is the corresponding dextrorotatory isomer. The latter compound, viz., d-6-fluoro-[chroman-4,4'-imidazolidine]-2',5'-dione or sorbinil, is the most preferred member of this series and is of the 4S-configuration. It is particularly useful as an aldose reductase inhibitor in man for preventing or alleviating certain diabetes-associated chronic complications, including those of an ocular or neuritic nature (e.g., diabetic cataracts, retinopathy and neuropathy, etc.).